Zygel Cannabidiol Gel Still Found Effective for Children in Interim Analysis

Zygel, an experimental cannabidiol gel developed by Zynerba Pharmaceuticals to ease abnormal behaviors in people with fragile X syndrome, was well tolerated and effective, including in patients with severe disease, according to a new interim analysis of an open-label extension study.

The poster, titled “Long-Term Safety and Sustained Efficacy of ZYN002 Cannabidiol Transdermal Gel in Children and Adolescents with Fragile X Syndrome (ZYN2-CL-017),” was presented at the International Society for Autism Research Annual Meeting (INSAR 2022).

The analysis included data from 240 patients, ages 3 to 17 years, followed up to February 2022 and enrolled in the long-term and open-label extension ZYN2-CL-017 study (NCT03802799).

Patients had previously participated in the placebo-control Phase 2/3 CONNECT-FX (NCT03614663) or the open-label Phase 2 FAB-C (ZYN2-CL-009) trials.

Safety data after a median treatment of 16 months (range 21–38 months) showed that Zygel was safe and well tolerated. Just 12.9% of patients reported treatment-related side effects, with the most common being application site pain, reported in 6.7% of participants. This, however, resolved quickly and was mild in the majority of cases (15 patients).

Six patients (2.5%) discontinued the therapy due to adverse effects. Seven patients experienced serious side effects, but none were related to Zygel.

Efficacy data were reported after a median 15 months of treatment in patients with a fully methylated FMR1 gene who completed the CONNECT-FX trial.

Methylation, a chemical modification that “turns off” a gene, is one of the alterations to the FMR1 gene that is mutated in fragile X. A full methylation of FMR1 is associated with a total absence of the FMRP protein and greater disease severity.

The results showed that Zygel eased patients’ behavioral symptoms, specifically social avoidance and irritability, as measured using the Aberrant Behavior Checklist-Community FXS (ABC-CFXS) — a caregiver-reported assessment of abnormal behaviors, including social avoidance, irritability, hyperactivity, and inappropriate speech.

According to Zynerba, these findings support the design of the Phase 3 RECONNECT trial (NCT04977986), which is recruiting children and adolescents, ages 3 to 17, mostly with a complete methylation of FMR1.

The trial, underway across clinical sites in the U.S., Australia, Ireland, and U.K., is currently recruiting participants.

This is considered a pivotal and confirmatory study, meaning that if successful, it will be used to support requests for approval.

“The interim results from this open-label extension trial support the long-term safety and effectiveness of Zygel in children and adolescents with Fragile X syndrome, with the greatest improvements seen in those with complete methylation of their FMR1 gene,” Armando Anido, chairman and CEO of Zynerba, said in a press release. “We are excited by the potential that Zygel may offer for patients with FXS.”

Zygel delivers cannabidiol (CBD) into the bloodstream through the skin, as a gel applied to the shoulder or upper arm. CBD is a nonpsychoactive compound found in the cannabis plant and is believed to modulate the endocannabinoid system.

Imbalances in this system may underlie some of the behavioral abnormalities common in fragile X. By restoring balance to the endocannabinoid system, Zygel might ease these symptoms in patients.